Studies in detoxication. 70. Metabolism of hydrazides and hydroxamic acids derived from salicylic acid

Abstract

A study was made of the fate of salicylohydrazide and its N-acetyl derivative, and of salicylo-hydroxamic acid and its 5-bromo derivative, in the rabbit. The last 2 compounds were also studied in man, rat and mouse. Salicylohydrazide is metabolized mainly by conjugation with glucuronic acid (55% of dose), and partly by hydrolysis to salicylic acid, which is excreted largely as salicyluric acid. N1-Acetyl-N2-salicyloyl-hydrazine is not deacetylated and is excreted mainly as its glucuronide (70% of the dose). These hydrazides do not form ethereal sulfates. Their glucuronides were isolated. Salicylohydroxamic acid is metabolized by direct conjugation with glucuronic and sulfuric acids in the rabbit, and there is practically no conversion into salicylamide. The glucuronide was isolated. In man, mouse and the rat, it forms considerable amounts of salicylamide, which is excreted conjugated. 5-Bromo-salicylohydroxamic acid is excreted by man, mouse, rabbit and rat mainly as conjugates of 5-bromosalicylamide, and to a lesser extent as the glucuronide of 5-bromosalicylohydroxamic acid. The glucuronides of the amide and the hydroxamic acid were isolated from rabbit urine. The in vitro tuberculostatic activity of 5-bromosalicylamide is about half that of 5-bromosalicylohydroxamic acid, its precursor in vivo. The toxicity of aroyl hydrazides and hydroxamic acids in relation to their metabolism is discussed.